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A proportion of prostate cancer (PCa) patients develop relapse following curative local treatment. Regional nodal recurrence is an emerging clinical situation since the introduction of new molecular imaging methods in the restaging of recurrent prostate cancer. More specifically, a subgroup of these patients is being diagnosed with a recurrence confined to the regional lymph nodes and limited in number (oligorecurrence) using choline or PSMA PET-CT. As there are no specific treatment recommendations for these type of patients, different treatment approaches are currently used, mostly focusing on local ablative treatments using radiotherapy or surgery. These treatments are coined metastasisdirected therapy (MDT). MDT in combination with or without temporary ADT could delay the subsequent risk of progression, and even cure limited regional nodal recurrences. Consequently, lifelong palliative ADT, with its toxicity and excess in non-cancer mortality might be postponed.

A proportion of prostate cancer (PCa) patients develop a local, regional (N1) or distant (M1) relapse following curative local treatment. For both local and distant relapses, different treatment recommendations are made in the guidelines (EAU guidelines 2016). However, the entity regional nodal recurrence is not mentioned in the guidelines but is an emerging clinical situation since the introduction of choline and more recently PSMA PET-CT in the restaging of recurrent prostate cancer. More specifically, a subgroup of these patients is being diagnosed with a recurrence confined to the regional lymph nodes and limited in number (oligorecurrence) using choline or PSMA PET-CT. As there are no specific treatment recommendations for these type of patients, different treatment approaches are currently used, mostly focusing on local ablative treatments using radiotherapy or surgery. These treatments are coined metastasisdirected therapy (MDT). MDT in combination with or without temporary ADT could delay the subsequent risk of metastases, and even cure limited regional nodal recurrences. Consequently, lifelong palliative ADT, with its toxicity and excess in non-cancer mortality might be postponed.

The proposed trial randomizes patients with oligorecurrent nodal prostate cancer following primary PCa treatment to either metastasis-directed therapy (MDT) (sLND or SBRT) or MDT plus WPRT. In the recurrent PCa setting, 2 recent trials have suggested a progression-free and even survival benefit of adding temporary ADT to local salvage prostate bed radiotherapy. Consequently, this positive effect might also be applicable for regional recurrences. Although the optimal duration of ADT is unknown, a minimal duration of 6 months of ADT seems advisable in this setting and will be mandatory for both arms.

This trial will improve our insights in the pattern of recurrence following these treatment modalities with the expectation that WPRT will reduce the number of nodal relapses, improving metastasis-free survival and postponing the need for palliative systemic treatments while maintaining quality-of-life. The current phase II trial will try to establish a golden standard in the treatment of oligorecurrent nodal PCa.

Metastasis-free survival will be defined as the time between randomization and the appearance of a metastatic recurrence (any M1) as suggested by choline, FACBC or PSMA PET-CT or death due to any cause

Secondary Outcome Measures :

Clinical Progression free survival [ Time Frame: 2 year ]

Clinical Progression-free survival is defined as time between randomization and the appearance of a new recurrence (any N1 or M1) as suggested by PET-CT, symptoms related to progressive PCa, or death due to any cause

Biochemical progression-free survival [ Time Frame: 2 year ]

For patients who had previous RP at initial diagnosis, a biochemical recurrence is defined by any confirmed PSA rise above 0.20 ng/ml with a confirmatory rise at least 2 weeks later. For patients who had previous RT to the prostate at initial diagnosis, a biochemical recurrence is defined as the nadir + 2ng/ml (Phoenix definition). Non-responders are considered to have a biochemical recurrence in case a second measurement at least 2 weeks later confirms a rising PSA

Toxicity: acute toxicity [ Time Frame: 3 months ]

Radiotherapy toxicity will be assessed according to NCI CTCAE v4.0.

Toxicity: late toxicity [ Time Frame: 2 year ]

Radiotherapy toxicity will be assessed according to NCI CTCAE v4.0.

quality of life [ Time Frame: 2 year ]

QOL will be assessed by the summary score of the scale for bowel symptoms included in the EORTC QLQ.

Scale name: PRBOW. Higher values represent a worse outcome. Total range of total score: 0-100. The items (ranging from 1 to 4 on a Likert-scale) were converted into values ranging from 0 to 100. A score of 100 can be interpreted as maximal bowel symptoms.

PR-25

Prostate cancer-specific survival [ Time Frame: 5 year ]

Cancer specific survival will be read as the time from trial randomization to the date of death due to prostate cancer

Overall survival [ Time Frame: 5 year ]

Overall survival will be read as the time from trial randomization to the date of death from any cause

Time to start of hormonal treatment [ Time Frame: 2 year ]

Time to hormonal treatment is defined as the time from trial randomization to start of hormonal treatment

Time to castration-resistant disease [ Time Frame: 5 year ]

Time to castration resistant disease is defined as the time from trial randomization until castration resistant status

economical evaluation [ Time Frame: 2 year ]

Assessment of quality-adjusted-life-years with the EuroQol classification system (EQ-5D-5L)

Sensitivity/specificity of PET-CT for the detection of nodal recurrences: limited to patients undergoing surgery [ Time Frame: 3 months ]

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Layout table for eligibility information

Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Histologically proven initial diagnosis of adenocarcinoma of the prostate

Following radical prostatectomy, patients with a biochemical relapse are eligible in case a nodal relapse is detected in the pelvis even in the absence of prior postoperative prostate bed radiotherapy (adjuvant or salvage).

In case of a suspected local recurrence following primary radiotherapy, a biopsy should confirm local recurrence and patients with a confirmed local recurrence are eligible in case they also undergo a local salvage therapy. If imaging rules out local relapse, patients are eligible.

Nodal relapse in the pelvis on choline, PSMA or FACBC PET-CT with a maximum of 3 positive nodal lymph nodes. The upper limit of the pelvis is defined as the aortic bifurcation.

WHO performance state 0-1

Age >18 years

Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

Bone or visceral metastases

Para-aortic lymph node metastases (above the aortic bifurcation)

Local relapse in the prostate gland or prostate bed not suitable for a curative treatment

Previous irradiation of the pelvic and or para-aortic nodes

Serum testosterone level <50ng/dl or 1.7 nmol/L at time of randomization